Treatment of a pediatric patient with concurrent neuroblastoma and acute lymphoblastic leukemia

To the Editor:

Leukemia is the most common type of childhood cancer, with a 5-year survival rate of 86.2%.¹ Neuroblastoma (NB) is the most common pediatric extracranial solid tumor, with a survival rate ranging from 62% to 98% dependent on risk classification.² Second malignancies of leukemia can occur following NB treatment; however, concurrent diagnoses of acute lymphoblastic leukemia (ALL) and NB have not been previously described. Coexistence of NB and Langerhans cell histiocytosis or acute myeloid leukemia have been reported, but the closest “simultaneous” NB and ALL were diagnosed 9 months apart.^3-5 Here, we describe a unique case of a patient treated for concurrent ALL and NB.

A 2-year-old male presented with limp, lymphadenopathy, and abdominal pain. Computed tomography (CT) identified a calcified mass arising from the adrenal gland. Lymphoblasts were identified on peripheral blood smear. Bone marrow studies demonstrated 90% lymphoblasts, and patient therefore diagnosed with low-risk B lymphoblastic leukemia (B-ALL). White blood cell count was 8.09 × 10⁹/L, no central nervous system (CNS) involvement, and next-generation sequencing revealed high-hyperdiploid (55–57 chromosomes; alterations of NRAS, PTPN11, and PAX5). The adrenal mass was resected; pathology showed unfavorable histology, MYCN nonamplified NB. A postoperative meta-iodobenzylguanidine (MIBG) scan identified two avid lymph nodes in the tumor bed. NB was staged as L1 disease and classified low risk. Figure 1 describes the following treatment plan.

Therapy for B-ALL was initiated as per St. Jude Total XVI protocol,⁶ with remission induction therapy (prednisone, vincristine, daunorubicin, peg-asparaginase, cyclophosphamide, mercaptopurine, cytarabine, and triple intrathecal chemotherapy [methotrexate, hydrocortisone, and cytarabine or “MHA”]). Day 15 bone marrow minimal residual disease (MRD) identified 0.375% lymphoblasts, and end-of-induction MRD was negative.

As the patient completed ALL remission induction therapy, comprehensive NB testing identified segmental copy number aberrations (SCAs) including 11q loss of heterozygosity (LOH), 17q gain, and 1p36 subclonal deletion. No germline cancer predisposition gene alterations were identified. Surveillance CT revealed local disease progression in the tumor bed. Subsequently, intermediate-risk NB treatment was initiated as per A3961 (carboplatin, etoposide, doxorubicin, cyclophosphamide).⁷ Concurrent oral dexamethasone and intrathecal chemotherapy were given for leukemia control while the patient received NB chemotherapy. Granulocyte colony-stimulating factor (G-CSF) was not administered due to risk of secondary hematological malignancy. Chemotherapy was dose adjusted for myelosuppression.

An NB disease evaluation demonstrated stable disease (SD), per revised International Neuroblastoma Response Criteria (INRC),⁸ with minimal anatomic improvement following the second chemotherapy cycle and persistent MIBG avidity. Thus, the patient underwent resection of left pararenal lymph nodes, eight total cycles of intermediate-risk NB chemotherapy, and proton radiation to tumor bed due to high risk of local recurrence in the setting of multiple SCAs.⁹ During radiation therapy, vincristine and dexamethasone were administered as interim leukemia therapy.

After completing NB therapy, consolidation and continuation therapy for ALL was planned, as per St. Jude Total XVI protocol.⁶ However, the patient experienced treatment toxicity (myelosuppression) during consolidation. Therefore, two cycles of blinatumomab were administered without significant complications. Blinatumomab was followed by continuation therapy as per low-risk Total XVI protocol (dexamethasone, vincristine, mercaptopurine, methotrexate, and peg-asparaginase).⁶ The patient completed ALL treatment 2.5 years following diagnosis.

The patient is 34 months post completion of NB therapy and 12 months post completion of ALL therapy without evidence of disease.

The treatment of a patient with two concurrent malignancies requires a unique therapeutic approach, combining therapies and modalities targeting both malignancies while mitigating toxicities. NB treatment can range from observation or resection only (low risk) to multimodal therapy requiring chemotherapy, surgery, radiation, myeloablative therapy with autologous stem cell transplant, immunotherapy, and isotretinoin (high risk). ALL therapy is also dictated by risk classification and may include some or all the following: chemotherapy, intrathecal chemotherapy, immunotherapy, chimeric antigen receptor (CAR) T-cell therapy, and allogeneic stem cell transplant. Two specific strategies can be learned from this case.

First, it is imperative to treat the disease with highest risk of rapid progression leading to worsened risk classification or death. In the referenced patient, at diagnosis the adrenal mass was localized with near complete surgical resection and lacked the most aggressive biologic feature (MYCN amplification). Therefore, risk of NB leading to acute clinical decompensation was lower than risks related to rapid ALL progression, and initial chemotherapy regimen targeted leukemia treatment. However, when surveillance imaging for NB demonstrated local NB progression (and three SCAs identified), the treatment paradigm shifted to address the actively progressing NB. In this case, intermediate-risk chemotherapy was given to treat NB and maintenance therapy administered to maintain ALL remission.

Second, therapy combinations used to treat both malignancies must be considered while mitigating overlapping toxicities. In this case, dexamethasone (to maintain leukemia remission) was successfully added to intermediate-risk NB chemotherapy, and vincristine plus dexamethasone (as leukemia maintenance) was tolerated during focal radiation for NB treatment. However, treatment required omission of certain aspects of therapy and replacement with alternative treatments. G-CSF typically used for myelosuppression following NB chemotherapy was omitted due to theoretical increased risk of secondary leukemia, leading to prolonged neutropenia requiring NB chemotherapy dosage reductions. Once the patient reached consolidation and continuation therapy for ALL, there was significant prolonged myelosuppression. Thus, immunotherapy (blinatumomab) was administered as a less myelosuppressive alternative consolidation given its known treatment effect in B-ALL.¹⁰

In summary, we describe the first successful treatment of a patient with concurrent ALL and NB. The treatment strategies required a unique therapeutic approach. However, combining therapies and modalities targeting both malignancies while mitigating toxicities was achieved. Similar approaches can be used for future rare patients requiring treatment for concurrent cancer diagnoses.

The authors declare they have no conflicts of interest.